Porous article of sintered calclium phosphate, process for producing the same and artificial bone and histomorphological scaffold using the same

ABSTRACT

The present invention provides porous material of calcium phosphate of high strength whose open pores penetrate the porous body and have a size of 70 μm or more, preferably 100 μm or more, and are arranged in a three-dimensional network, whose porosity is sufficiently high for blood vessels to invade and perforate itself or for cells to infiltrate itself, whose chemical composition, in particular, Ca/P molar ratio can be freely changed within the range of 0.75 to 2.1, to which elements important for facilitating osteogenesis and producing resorbable effect can be added, and whose phase composition can be relatively easily changed. The invention is porous sintered compact of calcium phosphate which has artificially formed, penetrated open pores 70 μm to 4 mm in diameter, whose porosity is from 20% to 80%, and whose chief ingredient is calcium phosphate having a Ca/P molar ratio of from 0.75 to 2.1.

TECHNICAL FIELD

The present invention relates to porous ceramics of calcium phosphate.The porous ceramics of calcium phosphate obtained in accordance withthis invention is used as substitute materials for tissue of livingbodies, tissue engineering scaffold and a drug carrier for DDS, all ofwhich are required to be biocompatible.

BACKGROUND ART

Conventional porous ceramics of calcium phosphate include: for example,porous ceramics which are produced by mixing a resin or organic matterwith calcium phosphate raw powder, forming the mixture into compact, andfiring the compact so that the portions of the sintered compact fromwhich the resin or organic matter has been removed provide pores (JPPatent Publication (Kokoku) Nos. 2-54303 B (1990), 7-88175 B (1995),8-48583 B (1996), and many others); which are produced by pouring aslurry to which a foaming agent has been added or a slurry in thefoaming state into a mold, drying the poured slurry, and sintering thedried slurry so that the resultant air bubbles provide pores (JP PatentPublication (Kokai) No. 5-270945 A (1993)); which are produced bypouring a slurry to which a foaming agent and a heat-shrinkable resinare added into a mold, drying the poured slurry, and sintering the driedslurry so that the resultant air bubbles provide pores (JP PatentPublication (Kokai) No. 2001-206787 A); which are produced by fillingcalcium phosphate dense particles into a compacting die, adding a slipformed of a mixture of metaphosphate, an organic binder and a solvent tothe compacting die, and sintering the particles together with the slipso that the solvent and the organic binder are removed to provide pores(JP Patent No. 3096930); which are produced by sintering acicularcalcium phosphate, set calcium phosphate hydrate or spherical calciumphosphate so that gaps among particles provide pores (JP PatentPublication (Kokai) Nos. 10-259012 A (1998), 9-309775 A (1997), 6-63119A (1994), 11-322458 A (1999)); which are produced by laminatingperforated green sheets of calcium phosphate and sintering the same sothat pores are formed (JP Patent Publication (Kokai) No. 11-178913 A(1999); which are produced by sintering calcium phosphate while applyinghigh voltage pulse (JP Patent Publication (Kokai) No. 11-35379 A(1999)); which are produced by integrating noodle-like extrudates ofapatite and sintering the integrated extrudates (JP Patent Publication(Kokai) No. 10-245278 A (1998)); which are produced by sinteringcancellous tissue of animals (JP Patent Publication (Kokai) No.2000-211978 A); which are produced by treating coral together withphosphoric acid by hydrothermal method so that pores are formed whileallowing the skeleton of the coral to be left (Roy D M et al., Nature247: 220-222 (1974)); which are produced by sintering a slurry ofcalcium phosphate that contains polyester fiber (Chang B S et al.,Biomaterials 21: 1291-1298 (2000)); which are produced by drying aslurry of calcium phosphate step by step to allow pores to communicatewith each other in a given direction and the sintering the dried calciumphosphate (JP Patent Publication (Kokai) No. 7-23994 A (1995)); whichare not sintered compact, but are produced by binding or attachingcalcium phosphate particles with polymer material and gaps among theparticles formed and perforations newly and mechanically made are usedas pores (JP Patent Publication (Kokai) Nos. 8-276003 A (1996),11-290447 A (1999)).

DISCLOSURE OF THE INVENTION

Of the above described processes for producing the porous materials ofcalcium phosphate, artificially synthesized porous materials, other thanthose produced using calcium phosphate from living organisms, havecommon problems. Specifically, in artificially synthesized conventionalporous materials of calcium phosphate, there is a problem of beingunable to increase the ratio of pores which penetrate the porousmaterials and have a diameter of 70 μm or more while maintaining theirstrength. In other words, there have been provided no artificiallysynthesized porous materials of calcium phosphate whose pores allpenetrate the porous materials and consist of large pores having adiameter of 70 μm or more and particularly 100 μm or more, whoseporosity is 50% or more, and besides whose strength is at a practicallysufficient level. Where the pores that penetrate porous materials are 70μm or less in diameter, where the pores take the form of a dead end anddo not penetrate porous materials, or where the pores are closed pores,even if such porous materials are embedded in tissues of livingorganisms, the invasion and penetration of blood vessels into the porousmaterials are restricted and thereby the furnishing of nutrition andoxygen is also restricted. This causes insufficient invasion of tissues,such as bone, into the porous materials, resulting in binding oftissues, such as bone, only to the peripheral portions of the porousmaterials. Furthermore, air having its escape cut off remains in theporous materials, which also contributes to inhibiting the invasion ofcells, tissues and blood vessels into the porous materials.

When porous materials that have dead-end and non-penetrating pores orclosed pores are used as a cell culture support, phenomenon occurs thatthe dead-end pores or closed pores are filled with air that has itsescape cut off and thereby the porous materials float on culture fluidmedia and do not sink in the media, or that neither cell culture medianor cells infiltrate into the dead-end pores or closed pores. As aresult, the application of such porous materials to the field of tissueengineering or regenerative medicine engineering, which aims at tissuereparation and organ regeneration by in-vitro culturing cells in porousmaterials of calcium phosphate and returning the cultured cells togetherwith the porous materials to the living bodies, has been restricted.

Low strength of artificially synthesized conventional porous materialsis attributed roughly to the following two points. The first point isthat since many of conventional porous materials are formed not bycompression press molding, but by the procedure of drying slurries ofpowder, the adhesion among powder particles results insufficient and theparticle adhesion after sintering is poor, whereby the strength is notincreased. The second point is that since the size and the arrangementof pores in conventional porous materials are disorderly, whencompressive load is applied, shearing force acts on anywhere in porewalls or beams that form the porous structure, whereby the beams and thewalls are fractured.

On the other hand, porous materials which have neither end-shaped poresnor closed pores, whose pores are all penetrating themselves and 70 μmor more in diameter, from which air is promptly expelled when they arein a liquid, and which allow good invasion and penetration of bloodvessels into themselves, and thus which are applicable to tissueengineering or regenerative medicine engineering are practically limitedto those of calcium phosphate from living organisms. The porousmaterials of calcium phosphate from living organisms use bones andcorals as raw materials. And in the porous structure of the tissues ofthese living organisms, the size of pores and the arrangement of beamsare orderly so that it undergoes not shear but buckling alone whencompressive load is applied thereto. As a result, porous materials ofcalcium phosphate from living organisms have high strength, despite thefact that all their pores consist substantially of those penetratingthemselves and 70 μm or more in diameter. The porous materials ofcalcium phosphate from living organisms thus have many excellent points;but on the other hand, they are at a disadvantage in that their chemicalcompositions and phase compositions cannot be selected freely and theirresorption and properties of facilitating tissue regeneration cannot becontrolled.

Accordingly the object of this invention is to provide a porous materialof calcium phosphate with high strength which has strength equal to orhigher than that of porous materials of calcium phosphate from livingorganisms; whose pores all penetrate itself and consist of large pores70 μm or more and preferably 100 μm or more in size so that it allowsair to be expelled from itself when it is in a liquid and blood vesselsto invade and perforate itself or cells to infiltrate into itself; whoseporosity is at a sufficient level; whose chemical composition can befreely changed so that Ca/P molar ratio varies within the range of 0.75to 2.1; to which elements important for facilitating osteogenesisactivity and producing resorption can be added; and whose phasecomposition can also be changed relatively easily.

In this invention, artificially formed, three-dimensional and penetratedopen pores mean those which are formed one by one using long columnarbodies as male dies, which have directional properties of penetrating asintered compact in two or more directions, whose beginning and endpositions are intentionally designed, which penetrate through thesintered compact, and whose spacing and arrangement are artificiallydesigned.

In this invention, to artificially form three-dimensional penetrate openpores, a large number of long columnar bodies having a cross-sectionalsize of 90 μm or more and 5.0 mm or less and preferably 100 μm or moreand 3.0 mm or less and having a length of 3-fold or more and preferably10-fold or more the cross-sectional size are used as male dies forforming pores. The materials for long columnar male dies are one kind ormore than one kind of solid selected from the group consisting of:metals; woods; bamboo or other plant materials; woods; carbon materials;halogen-free polymers having a modulus of elasticity of 10 GPa or more,such as polyethylene, nylon, polyacetal, polycarbonate, polypropylene,polyester, ABS, polystyrene, phenol, urea resin, epoxy resin andacrylate; and preferably halogen-free thermosetting polymers having amodulus of elasticity of 10 GPa or more, such as polyester, phenolresin, urea resin and epoxy resin. The reason for the use of these kindsof solid is that they have a high modulus of elasticity. Specifically,in this invention, since the long columnar male dies are pressurized at5 MPa or more and 500 MPa or less and preferably 10 MPa or more and 200MPa or less during the forming operation, if they have a modulus ofelasticity of 10 GPa or less, they themselves undergo a deformation of0.05% or more, which in turn causes fracture of the compact due to thepore closing during the pressurizing or due to the form restoration ofthe long columnar bodies after the pressurizing. If halogen-containingpolymers are used, the halogen reacts with calcium phosphate during thesintering to produce chlorine apatite (Ca₁₀(PO₄)₆Cl₂) or fluorineapatite (Ca₁₀(PO₄)₆F₂), which are poor in biocompatibility. Use ofthermosetting polymers makes it possible to avoid the reaction of thepolymers with the powder or binder used which is caused by their meltingand thereby decreases closing of pores during the firing.

The volume fraction of the long columnar bodies for forming penetratedopen pores to the compact obtained after compression molding is 20% ormore and 90% or less and preferably 30% or more and 80% or less. If thevolume fraction of the long columnar bodies to the compact after thecompression molding is less than 20%, a sufficient amount of cells andblood vessels are not allowed to be introduced into the pores of thecompact after sintering and the porous material obtained from thecompact is therefore practically of little value. If the volume fractionof the long columnar bodies to the compact after the compression moldingis more than 90%, the porous material obtained has markedly decreasedstrength and is not suitable for practical use.

The shape of the cross section of the long columnar bodies is notlimited to any specific one; however, a polygon having at least one pairof sides parallel to each other, an oval, a circle, or a figure formedof at least one pair of sides parallel to each other and curves isadvantageous in compression molding and drawing the long columnar bodiesout of the compact. The shape across the length of the long columnarbodies needs to be a rectilinear figure without a curve or a curvilinearor broken-line-like figure with curves on one plane alone. If it is acurvilinear figure with curves on two or more planes, it interferes withcompression molding, because a deformation is caused in the longcolumnar male dies during the compression molding, which in turn causesa fracture in the long columnar male dies as well as a fracture in thecompact due to the form restoration of the long columnar bodies afterpressurizing.

The size of the cross section of the long columnar male dies depends onthe pore size finally required. In artificial bones or porous materialsof calcium phosphate used for tissue engineering, pore size is neededafter sintering which allow at least more than one vascular endothelialcell or osteoblast 30 μm in size to invade one pore at a time. To allowthe pore size after sintering to be 70 μm or more, the cross-sectionalsize of the long columnar male dies needs to be 90 μm or more, becausepores shrink by 10 to 20% by sintering. In artificial bones or porousmaterials of calcium phosphate used for tissue engineering, it is notalways necessary to allow blood vessels 4 mm or more in size to invadetheir pores, and therefore, the cross-sectional size of the longcolumnar male dies need not be 5.0 mm or more, even taking intoconsideration 10 to 20% of pore shrinkage. For the reasons describedabove, the cross-sectional size of the long columnar male dies is 90 μmor more and 5.0 mm or less. The length of the long columnar male dies is3-fold or more and preferably 10-fold or more their cross-sectionalsize. If the length of the long columnar male dies is 3-fold or lesstheir cross-sectional size, when powder is added so that all the longcolumnar bodies used penetrate through the powder, the maximum size ofthe porous ceramics produced is restricted to about 10 mm, and porousmaterials having such size are of little value for practical use inartificial bones and tissue engineering.

To enhance the strength of the porous materials to be produced, firstthese long columnar male dies are arranged, powder is added, andpressure is applied to the plane on which the long columnar male diesare arranged to compress the powder. The long columnar male dies may bearranged parallel to each other at regular intervals, parallel to eachother at irregular intervals, or non-parallel to each other as long asthey do not overlap. They can be arranged radially so that a pluralityof long columnar male dies are concentrated on one spot from itssurroundings, multiply radial so that a plurality of long columnar maledies are concentrated on more than one spots from their surroundings, orresinoid. However, when the long columnar male dies are arrangedradially, multiply radial or resinoid, it is necessary to bring the endsurface portion of one long columnar male die completely into contactwith the end surface portions of the other long columnar male dies byfitting, bonding, etc. The portion which is incompletely in contact withthe other portions contributes to the formation of a pore having a deadend after sintering. The pressure applied during compression molding is5 MPa or more and 500 MPa or less and preferably 10 MPa or more and 200MPa or less. The reason for setting the pressure during compressionmolding in the above range is that if the pressure is 5 MPa or less, theadhesion among powder particles results insufficient, which makes itimpossible to produce a porous ceramic having sufficient strength,whereas if the pressure is 500 MPa or more, the long columnar male diesare more likely to deform or fracture. Further, if the pressure is 500MPa or more, when intending to draw the long columnar male dies out ofthe pressurized compact after the completion of stacking operation, themale dies cannot sometime be drawn out or they can sometimes be worn dueto the friction produced between the powder and themselves. This isproblematic when long columnar metal male dies are used.

In this invention, precursors of calcium phosphate mean calciumphosphate which becomes sintered compact of calcium phosphate aftersintering and the above calcium phosphate which contains at least oneselected from the group consisting of carbonic acid, silicon, magnesium,zinc, iron and manganese.

In this invention, “calcium phosphate in which elements or carbonic acidis dissolved” means: when one or more than one metal element such asmagnesium, zinc, iron or manganese are dissolved in calcium phosphate,calcium phosphate in which part of calcium is substituted with one ormore than one of the above elements as impurities; when silicon isdissolved in calcium phosphate, calcium phosphate in which part ofphosphorous is substituted with silicon as an impurity; and whencarbonic acid is dissolved in calcium phosphate, calcium phosphate inwhich part of phosphoric acid is substituted with carbonic acid as animpurity. When silicon or carbonic acid is dissolved in calciumphosphate, there is discrepancy between the charge of the atom or theion group to be replaced and that of silicon or carbonic acid; as aresult, secondary dissolution of other elements occurs or vacant siteswhere no atoms exist are produced in the structure so as to compensatethe discrepancy. For example, when carbonic acid is dissolved inhydroxyapatite Ca₁₀(PO₄)₆(OH)₂, simultaneous substitution of (Na⁺, CO₃²⁻) for (Ca²⁺, PO₄ ³⁻) or of (H⁺, CO₃ ²⁻) for (Ca²⁺, PO₄ ³⁻) occurs.Each element or ion group has a solubility limitation. As a result, whenintending to dissolve an element such as silicon, magnesium, zinc, ironor manganese in calcium phosphate beyond the solubility limit, the oxideor phosphate of such an element is formed, besides calcium phosphate inwhich the element is dissolved, and thus a composition is provided whichcontains the oxide or phosphate. In low-temperature-type Ca₃(PO₄)₂, thesolubility limits of magnesium, zinc, iron and manganese are all about12 mol % of the total amount of calcium.

As powders of calcium phosphate precursors, those whose Ca/P molar ratiois 0.75 or more and 2.1 or less and preferably 1.1 or more and 1.9 orless can be used. Even if the Ca/P molar ratio is 1.5 or less, incalcium phosphate precursors that contain an impurity selected from thegroup consisting of carbonic acid, silicon, magnesium, zinc, iron andmanganese, for example, in calcium phosphate precursors that containmagnesium, a mixture of magnesium dissolved tricalcium phosphate andtrimagnesium phosphate is formed and thus the formation of calciumpyrophosphate, which is poor in biocompatibility, can be prevented.However, if the Ca/P molar ratio is 0.75 or less, though addition of animpurity selected from the group consisting of carbonic acid, silicon,magnesium, zinc, iron and manganese enables the formation of calciumpyrophosphate to be prevented, the mole number of such an impuritybecomes larger than that of calcium and thereby resultant sinteredcompact is not that of calcium phosphate. Thus the minimum of the Ca/Pmolar ratio of the calcium phosphate precursor powders used is 0.75. Ifthe Ca/P molar ratio is 2.1 or more, calcium oxide is formed in amountsbeyond its toxic limit, and the biocompatibility of resultant porousmaterials after sintering deteriorates. Thus the maximum of the Ca/Pmolar ratio of the calcium phosphate precursor powders used is 2.1. Theparticle size of the calcium phosphate precursor powders used is notlimited to any specific one; however, preferably it is in the range ofabout 0.1 μm to 100 μm.

In calcium phosphate precursors that contain none of carbonic acid,silicon, magnesium, zinc, iron and manganese, preferably the Ca/P molarratio is 1.5 or more and 2.0 or less. Concrete examples of such calciumphosphate precursors are: hydroxyapatite; tricalcium phosphate;tetracalcium phosphate; amorphous calcium phosphate; each of whichindependently has a Ca/P molar ratio of 1.5 or more and 2.0 or less, andthe mixtures thereof; and besides, the powders of each of the abovedescribed compounds and mixtures with which powder having a Ca/P molarratio of 1.5 or more and 2.0 or less, for example, a calcium salt suchas calcium hydrogenphosphate, calcium glycerophosphate, metal calcium,calcium oxide, calcium carbonate, calcium lactate, calcium citrate,calcium nitrate or calcium alkoxide, ammonium phosphate, or phosphoricacid is mixed. These compounds may have a stoichiometric ornon-stoichiometric composition.

Concrete examples of calcium phosphate precursors that contain carbonicacid are: carbonic-acid-dissolved hydroxyapatite;carbonic-acid-dissolved amorphous calcium phosphate; the mixturethereof; and calcium phosphate precursors to which sodium carbonate,potassium carbonate or ammonium carbonate is added.

Concrete examples of calcium phosphate precursors that contain silicicacid are: silicic-acid-dissolved hydroxyapatite; silicic-acid-dissolvedamorphous calcium phosphate; silicic-acid-dissolved tricalciumphosphate; the mixtures thereof; and calcium phosphate precursors towhich calcium silicate or silicic acid is added.

Concrete examples of calcium phosphate precursors that containmagnesium, zinc, iron, or manganese are: hydroxyapatite, amorphouscalcium phosphate, tetracalcium phosphate and tricalcium phosphate inwhich metal ions as above are dissolved; and calcium phosphateprecursors to which one or more than one of the above metals, or themetal oxides, hydroxides, phosphates, nitrates or carbonates thereof isadded. The chlorides, fluorides and sulfates of the metals cannot beused because they allow chlorine, fluorine and sulfuric group, which arepoor in biocompatibility, to remain during sintering.

In this invention, “binder” means organic or inorganic substances havingbonding properties which are added to calcium phosphate precursors sothat the processes of forming and sintering the precursor powder aredone well. Concrete examples of such binders are polyvinyl alcohol andcarboxymethyl cellulose.

In this invention, “solvent” means substances that are added to calciumphosphate precursors so that the flowability and adhesion of theprecursors are improved. Concrete examples of such solvents are water,alcohols, and other volatile organic solvents.

The amount of calcium phosphate precursor powder added needs to beweighed out so that it is 103% or more and less than 114% and preferably104% or more and 106.5% or less of the amount of calcium phosphatepowder calculated from the equation (volume of the clearance among longcolumnar bodies)×(theoretical value of calcium phosphate density). Ifthe amount is 103% or less, the powder is hard to pressurize. If theamount is 114% or more, the column surface of the long columnar bodiesis completely buried in the powder and does not come in contact with theadjacent long columnar bodies during the stacking process describedbelow. In this case, after pressurizing the powder, excess powder isremoved from each of the long columnar bodies so that the powder and thelong columnar bodies are at the same level.

If the powder is added in amounts within the preferable range, that is,104% or more and 106.5% or less, part of the surface of each longcolumnar bodies is exposed, which makes it possible to form continuouspores extending at right angles with the plane on which the longcolumnar bodies are oriented. However, even when the powder is added inamounts within the preferable range, 104% or more and 106.5% or less, itis better to carry out the step of removing excess powder from each ofthe long columnar bodies so that the powder and the columnar bodies areat the same level, because the step allows much more pores tocontinuously extend at right angles with the plane on which the longcolumnar bodies are oriented.

As a binder added to the calcium phosphate precursor powder, polyvinylalcohol can be used and its amount is 2 wt % or more and 10 wt % or lessand preferably 2 wt % or more and 5 wt % or less, just like the case ofordinary compression molding of calcium phosphate. If the amount ofpolyvinyl alcohol added is 10 wt %, the walls or beams of the porousmaterials after sintering become porous, which means insufficientimprovement in strength. If the amount of polyvinyl alcohol added is 2wt % or less, the adhesion among the powder particles is poor andthereby compression molding is impossible. Preferably the amount ofsolvent added is 5 wt % or more and 52 wt % or less and preferably 10 wt% or more and 45 wt % or less. Addition of a solvent improves theflowability of the powder and thereby the clearance among the longcolumnar male dies can be filled with the powder during the pressurizingof the powder. When a solvent is added, a drying step for evaporatingthe solvent is carried out before the sintering step. The reason forsetting the amount of solvent added at 5% or more and 52% or less isthat if the amount is 5% or less, the solvent-added powder ispractically the same as a dry powder and the effect of adding a solventcannot be produced, whereas if the amount is 52% or more, the walls orbeams of the porous materials after sintering become porous, which meansinsufficient improvement in strength.

A plurality of single-layer compression molded products are stackedwhich are produced using a calcium phosphate precursor, or a compositionmade up of a calcium phosphate precursor and a binder, or a compositionmade up of a calcium phosphate precursor, a binder and a solventdepending on the situation. The stacking process may be carried out insuch a manner as to prepare a plurality of single-layer molded productsin advance and stack them at a time or in such a manner as tocompression mold one single-layer product and mold another single-layerproduct on the above single-layer product. In the stacking process, aplurality of single-layer products are stacked so that each of the longcolumnar male dies in one single-layer product comes in contact withvertically adjacent long columnar male dies at more than one point andthe long columnar male dies in one single-layer product extend in thedirection different from that in which the long columnar male dies inadjacent single-layer products do. Thus, the contact points among thelong columnar male dies form continuous pores extending in thedie-stacked direction. The pressure applied during the compressionmolding is 5 MPa or more and 500 MPa or less and preferably 10 MPa ormore and 200 MPa, just like the case of the single-layer formingprocess.

To enhance the functions of living bodies, one kind or more than onekind of element, which is selected from the group consisting of zinc,magnesium, iron, manganese and silicon, essential to living bodies canbe added to the calcium phosphate precursors. The content of zinc, iron,manganese or silicon in the porous ceramics after sintering should be inthe range of 1-fold to 100-fold the content of the same in bone. Thecontents of zinc, iron, manganese and silicon in bone are as follows.Zinc: 0.012 wt % to 0.0217 wt %, iron: 0.014 wt % to 0.02 wt %,manganese: 1 ppm to 4 ppm, and silicon: 0.0105 wt %. If the content suchan element in porous materials is less than 1-fold the content of theelement in bone, the effect of facilitating the function of livingbodies specific to the element cannot be produced. If the content ofsuch an element in porous materials is more than 100-fold the content ofthe element in bone, the element exists in excess both in bone tissueand in tissue engineering scaffold used in a cell culture medium anddevelops toxicity. If the content of such an element in porous materialsis 25-fold or more and 100-fold or less the content of the element inbone, the element develops toxicity in bone tissue, but not in a cellculture medium and thus the porous materials cab used as a tissueengineering scaffold. The content of magnesium in porous materials aftersintering should be in the range of 1-fold to 50-fold the content ofmagnesium in bone. The content of magnesium in bone is 0.26 wt % to 0.55wt %. If the content of magnesium in porous materials is 1-fold or lessthe content of the same in bone, the effect of facilitating the functionof living bodies specific to magnesium cannot be produced. The reasonfor setting the maximum of the magnesium content in porous materials at50-fold the magnesium content in bone, unlike the other elementessential to living bodies, is that the content of magnesium in bone isfar large compared with the other elements, and therefore, if themagnesium content in porous materials is 50-fold or more of that inbone, the mole number of magnesium becomes larger than that of calciumin the porous materials after sintering, which means the main componentof the porous materials is not calcium phosphate.

The above described elements essential to living bodies may be dissolvedin calcium phosphate crystal that makes up the powder of calciumphosphate precursor or may be mixed with the same in the form of aninorganic salt, metal, oxide, hydroxide or organometallic compound. Whensuch inorganic salts, metals, oxides, hydroxides or organometalliccompounds are mixed with calcium phosphate crystal in advance, suchelements react with calcium phosphate and are dissolved in the sameduring sintering. The amount of such an element mixed is beyond itssolubility limit, besides the element-dissolved calcium phosphate, itsmetal oxide or phosphate is also produced. When such an element is mixedin the form of an inorganic salt, it is preferable for the element totake the form of a carbonate or nitrate whose negative ion groupvolatiles during sintering.

To accelerate the disappearance of porous sintered calcium phosphate,which is dissolved and resorbed in living bodies with the passage oftime, the powder of calcium phosphate precursor is allowed to containcarbonic acid. The carbonic acid content in the calcium phosphate aftersintering is in the range of 0.3 wt % to 5 wt % in terms of CO₃ ²⁻. Thecarbonic acid content of 0.3 wt % corresponds to that of bone-likeapatite, and with the content equal to or less than 0.3 wt %, calciumphosphate shows more tendency toward precipitating and is unlike to bedissolved/absorbed into living bodies. If the carbonic acid content is15 wt % or more, it is hard to keep the calcium phosphate phase stable.Since many of carbonates are decomposed at high temperatures and scatterand lose carbonic acid, to allow calcium phosphate precursors to containcarbonic acid, it is preferable to use carbonated apatite obtained bysimultaneously substituting the Ca and PO₄ sites of hydroxyapatiteCa₁₀(PO₄)₆(OH)₂ with Na and CO₃ or to add sodium carbonate as anadditive.

When the long columnar male dies in the compression molded productformed through the single-layer forming process and the long columnarbodies are formed of metal, they should be drawn out and removed afterthe layer-stacking process without failure. When the long columnar maledies are formed of other materials such as bamboo, woods, carbonmaterials, or polymers, they may also be drawn out after thelayer-stacking process; however, even if they are kept buried in thepowder, they disappear during firing.

When water is added to the powder before compression molding, theresultant compression molded product is dried at room temperature aftercompleting the layer-stacking process until no change is observed in itsweight. The drying temperature is not specified, but it is preferable todry the molded product at room temperature or lower. At dryingtemperatures of 50° C. or higher, when the molded product containspolyvinyl alcohol as a binder, the polyvinyl alcohol degenerates. As aresult, the sintered density of the molded product is not increased evenby sintering and peeling is more likely to occur at stacking interfaces.At drying temperatures of 40° C. or higher, peeling at stackinginterfaces can sometimes occur.

The process of sintering the compression molded product is carried outin atmosphere at 500° C. or higher and 1500° C. or lower and preferably700° C. or higher and 1400° C. or lower in an ordinary electric furnace.If the temperature is 500° C. or lower, sintering does not occur,whereas if the temperature is 1500° C. or higher, much of calciumphosphate is decomposed. The optimal sintering temperature variesdepending on the chemical composition of the calcium phosphate powder tobe sintered. For example, the optimal sintering temperature ofhydroxyapatite containing 3 to 15 wt % of carbonic acid is 600° C. orhigher and 800° C. or lower. The optimal sintering temperature ofhydroxyapatite (Ca₁₀(PO₄)₆(OH)₂: Ca/P molar ratio=1.67) is 900° C. orhigher and 1200° C. or lower. The optimal sintering temperature ofhydroxyapatite containing silicon is 900° C. or higher and 1200° C. orlower. The optimal sintering temperature of low-temperature typetricalcium phosphate (Ca₃(PO₄)₂: Ca/P molar ratio=1.50) is 900° C. orhigher and 1100° C. or lower. The optimal sintering temperature oflow-temperature type tricalcium phosphate containing zinc, manganese ormagnesium is 900° C. or higher and 1200° C. or lower. The optimalsintering temperature of high-temperature type tricalcium phosphatecontaining zinc, manganese or magnesium is 1300° C. or higher and 1500°C. or lower.

After completing the sintering process, the density can be measured todetermine the porosity. The state where pores are in communication witheach other can be assessed by observation under microscope, stereoscopeor electron microscope or through staining liquid infiltration. Thecompressive strength of the porous sintered calcium phosphate can beassessed using Instron type universal tester.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photograph showing the external appearance of a poroussintered compact after firing, whose outside dimensions are 8 mm×8 mm×3mm;

FIG. 2 is an electron micrograph showing the pores of a porous sinteredcompact after firing; and

FIG. 3 is a micrograph showing bony tissue formed in the interior of aporous material.

BEST MODE FOR CARRYING OUT THE INVENTION

In the following, this invention will be described in more detail bymeans of examples.

EXAMPLE 1

After weighing out 0.175 g of hydroxyapatite powder (Ca₁₀O(PO₄)₆(OH)₂:Ca/P molar ratio 1.67) under 75 μm in particle size to which 3%polyvinyl alcohol had been added, 65 microliter of ultra pure water wasadded to and mixed with the powder. Thirteen long columnar stainlesssteel male dies 0.5 mm in diameter 28 mm in length were arrangedparallel to each other at intervals of 0.3 mm, and 14 long columnarstainless steel male dies of the same size as above were arranged on theabove male dies at right angles with the same. The above long columnarmale die arrangement was packed with the above powder mixture andpressurized at 36 MPa. After the pressurization, powder that coated thelong columnar male dies was removed with a plastic scraper. The aboveoperation was repeated 4 times. After the compression molding, all thelong columnar male dies were drawn out to form pores in the compressionmolded product. The compression molded product was dried for 2 days atroom temperature and then sintered for 5 hours at 1170° C. to give aporous sintered compact. After the sintering, the porous sinteredcompact shrank to produce a porous sintered compact in which linearpenetrated open pores 380 μm in diameter were spaced at intervals of 200μm and layers of the linear penetration alternately lay at right angleswith each other (refer to FIG. 1). The intersections of the linear poresextending in the respective two directions formed pores 50 to 200 μm indiameter; thus, not only the pores as replicas of the long columnar maledies but also continuous pores were formed in the die-stacked direction(refer to FIG. 2). Some of the intersections, however, were closed andthus the pores in the die-stacked direction were not necessarilypenetrating the porous sintered compact, even though they were openpores. The porosity of the porous sintered compact, as an average of 11compacts, was 61±3%. This porosity was almost equal to that of theporous apatite obtained by treating coral by hydrothermal method. TheSEM observation showed that the structure had fewer pores at its beamportion. A test was performed for the compressive strength of the poroussintered compact in the direction perpendicular to the die-stackeddirection, in which the strength of the compact was lowest. The measuredresult of the compressive strength was 10 MPa or higher, which was equalto or higher than that of the porous apatite from coral.

EXAMPLE 2

After weighing out 0.175 g of hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂: Ca/Pmolar ratio 1.67) powder under 75 μm in particle size to which 3%polyvinyl alcohol had been added, 65 microliter of ultra pure water wasadded to and mixed with the powder. Thirteen long columnar bamboo orpolystyrene male dies 0.5 mm in diameter 30 mm in length were arrangedparallel to each other at intervals of 0.3 mm, and 14 long columnarbamboo or polystyrene dies of the same size as above were arranged onthe above male dies at right angles. The above long columnar male diearrangement was packed with the above powder mixture and pressurized at36 MPa. After the pressurization, powder that coated the long columnarmale dies was removed with a plastic scraper. The above operation wasrepeated 4 times. After the compression molding, the compression moldedproduct was dried for 2 days and then sintered for 5 hours at 1170° C.to give a porous sintered compact. Both the long columnar bamboo maledies and the long columnar polystyrene male dies were burned down duringthe sintering process. After the sintering, the porous sintered compactobtained using the long columnar bamboo male dies shrank to produce aporous sintered compact in which linear penetrated open pores 380 μm indiameter were spaced at intervals of 200 μm and layers of the linearpenetrated open pores alternately lay at right angles with each other.On the other hand, the porous sintered compact obtained using the longcolumnar polystyrene male dies partly collapsed because of thedistortion of polystyrene during the compression molding operation andthe form restoration at an early stage of heating at 200° C. or less.

EXAMPLE 3

After weighing out 0.175 g of each of different kinds of calciumphosphate precursor powders, different in Ca/P molar ratio, under 75 μmin particle size to which 3% polyvinyl alcohol had been added, 40 to 65microliter of ultra pure water was added to and mixed with eachprecursor powder. Thirteen long columnar stainless steel male dies 0.5mm in diameter 28 mm in length are arranged parallel to each other atintervals of 0.3 mm, and 14 long columnar stainless steel male dies ofthe same size as above are arranged on the above male dies at rightangles with the same. The above long columnar male die arrangement waspacked with the above powder mixture and pressurized at 36 MPa. Afterthe pressurization, powder that coated the long columnar male dies wasremoved with a plastic scraper. The above operation was repeated 4times. After the compression molding, all the long columnar male dieswere drawn out to form pores. The compression molded product was driedfor 2 days at room temperature and then sintered for 5 hours at 1100 to1170° C. to give a porous sintered compact. After the sintering, theporous sintered compact shrank to produce a porous sintered compact inwhich layers of linear penetrated open pores alternately lay at rightangles. The intersections of the linear pores extending in the tworespective directions formed pores 50 to 200 μm in diameter; thus, notonly the pores as replicas of the long columnar male dies but alsocontinuous pores were formed in such a direction that the long columnarmale dies were stacked. Some of the intersections, however, were closed.The results are shown in Table 1. When 500 microliter of staining liquidis infiltrated into the resultant porous sintered compacts 8 mm×8 mm×3mm in overall size, the staining liquid perforated to the back side ofthe sintered compact in any direction within 1 to 3 seconds. Thisindicated that the pores completely penetrated the sintered compact andthere was no factor that inhibits the invasion of cells, tissue andblood vessels into the porous sintered compact. TABLE 1 Ca/P Amount ofSintering Pore molar water added temperature diameter Porosity Precursorratio (μl) (° C.) (μm) (%) HAP + TCP 1.60 65 1100 400 64 HAP + TCP 1.6465 1100 400 65 TCP 1.50 40 1100 400 59 HAP + CC 1.81 45 1170 380 65HAP: hydroxyapatite Ca₁₀(PO₄)₆(OH)₂TCP: tricalcium phosphate Ca₃(PO₄)₂CC: calcium carbonate CaCO₃

EXAMPLE 4

After weighing out 0.175 g of each of different kinds of calciumphosphate precursor powders under 75 μm in particle size to which 3%polyvinyl alcohol containing elements essential to living bodies hadbeen added, 65 to 80 microliter of ultra pure water was added to andmixed with each precursor powder. Thirteen long columnar stainless steelmale dies 0.5 mm in diameter 28 mm in length are arranged parallel toeach other at intervals of 0.3 mm, and 14 long columnar stainless steelmale dies of the same size as above are arranged on the above male diesat right angles with the same. The above long columnar male diearrangement was packed with the above powder mixture and pressurized at36 MPa. After the pressurization, powder that coated the long columnarmale dies was removed with a plastic scraper. The above operation wasrepeated 4 times. After the compression molding, all the long columnarmale dies were drawn out to form pores. The compression molded productwas dried for 2 days at room temperature and then sintered for 5 hoursat 1100° C. to give a porous sintered compact. After the sintering, theporous sintered compact shrank to produce a porous sintered compact inwhich layers of linear penetrated open pores alternately lay at rightangles. The intersections of the linear pores extending in the tworespective directions formed pores 50 to 200 μm in diameter; thus, notonly the pores as replicas of the long columnar male dies but alsocontinuous pores were formed in the die-stacked direction. Some of theintersections, however, were closed. The resultant porous sinteredcompacts were white, but one to which iron was added was light brown.The results are shown in Table 2. TABLE 2 Metal content Pore diameterPorosity Precursor Ca/P (wt %) (μm) (%) HAP + TCP + ZnTCP 1.61 0.84 40065 HAP + TCP + ZnTCP 1.57 1.20 400 62 HAP + TCP + MgTCP 1.48 2.2 400 76MgTCP + TMP 1.12 6.1 400 75 HAP + TCP + Fe 1.60 0.5 400 64HAP: hydroxyapatite Ca₁₀(PO₄)₆(OH)₂TCP: tricalcium phosphate Ca₃(PO₄)₂ZnTCP: 10 mol % zinc-tricalcium phosphate solid solutionCa_(2.7)Zn_(0.3)(PO₄)₂MgTCP: 10 mol % Mg-tricalcium phosphate solid solutionCa_(2.7)Mg_(0.3)(PO₄)₂TMP: trimagnesium phosphate Mg₃(PO₄)₂Fe: iron hydroxide

EXAMPLE 5

As calcium phosphate precursors, were used carbonated hydroxyapatitepowders under 75 μm in particle size which contained 12.5 wt % ofcarbonate and 7.1 wt % carbonate, respectively. Both kinds of carbonatedhydroxyapatite were precipitates obtained by mixing an aqueous solutioncontaining phosphate ions, an aqueous solution containing calcium ionsand sodium carbonate. Carbonate group was substituted for part of thephosphate group of hydroxyapatite and sodium was substituted for part ofthe calcium of hydroxyapatite. After weighing out 0.175 g of each kindof hydroxyapatite powder, 40 microliter of ultra pure water was added toand mixed with the hydroxyapatite. No binder was added. Thirteen longcolumnar stainless steel male dies 0.5 mm in diameter 28 mm in lengthare arranged parallel to each other at intervals of 0.3 mm, and 14 longcolumnar stainless steel male dies of the same size as above arearranged on the above male dies at right angles. The above long columnarmale die arrangement was packed with each of the above powder mixtureand pressurized at 36 MPa. After the pressurization, powder that coatedthe long columnar male dies was removed with a plastic scraper. Theabove operation was repeated 4 times. After the compression molding, allthe long columnar male dies were drawn out to form pores. Thecompression molded product was dried for 2 days and then sintered for 5hours at 630° C. to give a porous sintered compact. The carbonatecontent after the sintering was decreased by about 6% because part ofcarbonate group volatilized and scattered due to the sintering. Afterthe sintering, the porous sintered compact shrank to produce a poroussintered compact in which layers of linear penetrated open poresalternately lay at right angles. The intersections of the linear poresextending in the two respective directions formed pores 50 to 200 μm indiameter; thus, not only the pores as replicas of the long columnar maledies but also continuous pores were formed in the die-stacked direction.Some of the intersections, however, were closed. The results are shownin Table 3. TABLE 3 Carbonate content after sintering Pore diameterPorosity Precursor Ca/P ratio (wt %) (μm) (%) CO3AP12 1.97 6 400 65CO3AP7 1.81 1 400 62CO3AP 12: 12.5 wt % carbonated hydroxyapatite solid solutionCO3AP 7: 7.1 wt % carbonated hydroxyapatite solid solution

EXAMPLE 6

Porous hydroxyapatite having linear penetrated open pores, which wasobtained in example 1, and porous hydroxyapatite from coral were drysterilized for 1 hour at 160° C. The pore diameter and porosity of theporous hydroxyapatite having linear penetrated open pores and the poroushydroxyapatite from coral used are shown in Table 4. Both were almostequal in porosity. Femurs of Fischer 344 strain male rats aged 7 weekswere cut off at their both ends and the marrow cells within the femurswere washed out with 10 mL of cell culture medium. The bone marrow cellstaken out of the femurs were cultured for 9 days in Eagle-MEM containing15% fetal bovine serum, 100 units/mL of penicillin, 100 μg/mL ofstreptomycin and 0.25 μg/mL of amphotericin B. After the culture, thecells were treated with 0.1% trypsin and cell suspension of 1×10⁷/mL wasprepared. The above sterilized porous hydroxyapatite having linearpenetrated open pores and porous hydroxyapatite from coral were immersedin the cell suspension. Then both kinds of porous hydroxyapatite wereimplanted into subcutaneous tissue of the dorsa of Fischer 344 strainmale rats. Both kinds of implanted porous hydroxyapatite were extractedafter 4 weeks and the activity of alkaline phosphatase, an index ofosteogenesis activity of osteoblast, was measured as an osteoblastdifferentiation marker for each kind of porous hydroxyapatite. And theamount of bone Gla-protein, an index of the amount of newly formed bone,was also measured. The measured values of the alkaline phosphataseactivity and the amount of bone Gla-protein were each divided by theweight of porous hydroxyapatite. Comparison was made between theresultant values of the porous hydroxyapatite having linear penetratedopen pores and the porous hydroxyapatite from coral (n=4). The resultsare shown in Table 5 and Table 6. No significant differences in value ofthe alkaline phosphatase activity were found between the poroushydroxyapatite having linear penetrated open pores and poroushydroxyapatite from coral. No significant differences in amount of boneGla-protein per unit weight were found, either, between both kinds ofporous hydroxyapatite. These indicate that the porous hydroxyapatitehaving linear penetrated open pores in accordance with this inventionhas biocompatibility and bioactivity equivalent to those of the poroushydroxyapatite from coral, which has been already used as artificialbone and tissue engineering scaffold, and thus can be used as bothartificial bone and tissue engineering scaffold. The extracted poroushydroxyapatite having linear penetrated open pores was fixed,decalsified and cut to thin slices, and the bony tissue formed withinthe porous hydroxyapatite was stained by hematoxylin-eosin staining andused as decalcified tissue specimens for microscopic observation. Thespecimens were observed under microscope and whether bony tissue wasformed within the porous hydroxyapatite or not was examined (refer toFIG. 3). The observation revealed that the porous hydroxyapatite causedno inflammation-related reaction and had high biocompatibility. Furtherthe observation confirmed excellent osteogenisis around the interior ofthe porous hydroxyapatite and that the porous hydroxyapatite havinglinear penetrated open pores in accordance with this invention could beused as both artificial bone and tissue engineering scaffold. TABLE 4Pore diameter (μm) Porosity x direction y direction z direction (%)Porous ceramic 380 380 50-200 61 having linear penetrated open poresPorous ceramic 190-230 50-65 from coral

TABLE 5 Alkaline phosphatase quantitated per unit Standard weight (micromol/mg) deviation Porous ceramic having 0.0333 0.0273 linear penetratedopen pores Porous ceramic from coral 0.0338 0.0114

TABLE 6 Amount of bone Gla-protein per unit weight Standard (ng/mg)deviation Porous ceramic having linear 1.37 0.73 penetrated open poresPorous ceramic from coral 2.84 2.82

Industrial Applicability

As described so far, in accordance with this invention, is providedporous material of calcium phosphate of high strength which has strengthequivalent to or higher than that of porous material of calciumphosphate from living organisms, whose pores consist of thosepenetrating itself and having a size of 70 μm or more, whose pores arearranged in a three-dimensional network, whose porosity is sufficientlyhigh for blood vessels to invade and perforate itself or for cells toinfiltrate itself, whose chemical composition, in particular, Ca/P molarratio can be freely changed from 0.75 to 2.1, to which elementsimportant for facilitating osteogenesis and producing resorbable effectcan be added, and whose phase composition can be relatively easilychanged. Thus the porous material of calcium phosphate in accordancewith this invention can be used as artificial bone.

The entire disclosure of the publications cited so far is incorporatedin this specification. Those skilled in the art will recognize thatvarious modifications and changes can be made in this invention withoutdeparting from the spirit or scope of the following claims. Thisinvention is intended to encompass these modifications and changes.

1. Porous sintered compact of calcium phosphate, comprising artificiallyformed, three-dimensional and perforated open pores from 70 μm to 4 mmin diameter, wherein the porosity is from 20% to 80%, and includingcalcium phosphate having a Ca/P molar ratio of 0.75 to 2.1 as a maincomponent.
 2. The porous sintered compact of calcium phosphate accordingto claim 1, wherein the calcium phosphate has at least one selected fromthe group consisting of carbonic acid, silicon, magnesium, zinc, ironand manganese dissolved therein.
 3. The porous sintered compact ofcalcium phosphate according to claim 1, comprising at least one oxide orphosphate of a metal selected from the group consisting of calcium,magnesium, zinc, iron and manganese, in addition to calcium phosphate.4. The porous sintered compact of calcium phosphate according to claim 2or 3, wherein the zinc content after sintering is from 0.012 wt % to 1.2wt %.
 5. The porous sintered compact of calcium phosphate according toclaim 2, wherein the carbonic acid content after sintering is from 0.3wt % to 15 wt %.
 6. The porous sintered compact of calcium phosphateaccording to claim 2 or 3, wherein the magnesium content after sinteringis from 0.26 wt % to 13 wt %.
 7. The porous sintered compact of calciumphosphate according to claim 2 or 3, wherein the silicon content aftersintering is from 0.0105 wt % to 1.05 wt %.
 8. The porous sinteredcompact of calcium phosphate according to claim 2 or 3, wherein the ironcontent after sintering is from 0.014 wt % to 1.4 wt %.
 9. The poroussintered compact of calcium phosphate according to claim 2 or 3, whereinthe manganese content after sintering is from 1 ppm to 100 ppm byweight.
 10. The porous sintered compact of calcium phosphate accordingto any one of claims 1 to 9, wherein the artificially formed, penetratedopen pores from 70 μm to 4 mm in diameter arranged in athree-dimensional network.
 11. The porous sintered compact of calciumphosphate according to any one of claims 1 to 10, wherein the crosssection of the penetrated open pores takes the form of a circle, oval orpolygon or has an external form created by a combination thereof.
 12. Aprocess for producing porous sintered compact of calcium phosphate,comprising the steps of: arranging rectilinear long columnar bodies orcurvilinear or broken-line-like long columnar bodies with curves on oneplane alone on the same plane so that they do not overlap with eachother; arranging additional rectilinear long columnar bodies orcurvilinear or broken-line-like long columnar bodies with curves on oneplane alone on the plane where the rectilinear long columnar bodies orcurvilinear or broken-line-like long columnar bodies with curves on oneplane alone have been already arranged so that the additional longcolumnar bodies do not overlap with each other and extend in thedirection different from that in which the long columnar bodiespreviously arranged extend; stacking the long columnar bodiesarrangements to form a layered structure thereof; placing a compositioncomprising a calcium phosphate precursor in the layered structure of thelong columnar bodies arrangements so that all the long columnar bodiespenetrate each powder of said composition; compression molding thepowder at 5 MPa to 500 MPa so that the long columnar bodies on one planeextend in the direction different from those in which the long columnarbodies on the vertically adjacent two planes extend and come in directcontact with the same; and sintering the compression molded product inoxidizing atmosphere at 500° C. to 1300° C.
 13. The process forproducing porous sintered compact of calcium phosphate according toclaim 12, wherein the composition comprising a calcium phosphateprecursor further comprises a binder.
 14. The process for producingporous sintered compact of calcium phosphate according to claim 13,wherein in the composition comprising a calcium phosphate precursor anda binder, at least one of the calcium phosphate precursor and the binderis allowed to contain a solvent in advance.
 15. The process forproducing porous sintered compact of calcium phosphate according to anyone of claims 12 to 14, wherein the volume fraction of the long columnarbodies is 20% to 90% of the compression molded product and thecompression molded product is sintered in oxidizing atmosphere at 500°C. to 1300° C.
 16. The process for producing porous sintered compact ofcalcium phosphate according to any one of claims 12 to 14, wherein thevolume fraction of the long columnar bodies is 20% to 90% of thecompression molded product and the compression molded product issintered in oxidizing atmosphere at 500° C. to 1300° C. after physicallyor chemically removing the long columnar bodies after molding at 100° C.or lower.
 17. The process for producing porous sintered compact ofcalcium phosphate according to any one of claims 12 to 16, wherein therectilinear long columnar bodies or curvilinear or broken-line-like longcolumnar bodies with curves on one plane alone whose cross section isany one selected from the group consisting of a circle, an oval and apolygon are made up of one or more materials selected from the groupconsisting of metals, woods, bamboo or other plant materials, carbonmaterials and halogen-free polymers having a modulus of elasticity of 10GPa or more.
 18. The process for producing porous sintered compact ofcalcium phosphate according to any one of claims 12 to 17, wherein themaximum diameter of the rectilinear long columnar bodies or curvilinearor broken-line-like long columnar bodies with curves on one plane aloneis 90 μm to 5.0 mm.
 19. Artificial bone using the porous sinteredcompact of calcium phosphate according to any one of claims 1 to
 11. 20.A process for producing artificial bone using the process for producingporous sintered compact of calcium phosphate according to any one ofclaims 12 to
 18. 21. A scaffold for tissue engineering using the poroussintered compact of calcium phosphate according to any one of claims 1to
 11. 22. A process for producing a scaffold for tissue engineeringusing the process for producing porous sintered compact of calciumphosphate according to any one of claims 12 to 18.